Transcriptional Regulation of Dormancy and Emergence in Breast Cancer

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Breast cancer ranks second among cancer deaths in women in the United States. Breast cancer-related mortality primarily results from metastatic growth of disseminated cells. While dissemination of cancer cells occurs early during tumor progression, metastatic outgrowth of extravasated cancer cells often takes many years due to the dormant behavior of cancer cells. In principle, the survival of breast cancer patients should be improved if metastatic burden is reduced by either prolonging the dormancy of disseminated tumor cells or slowing down progressive metastatic growth. Our overarching goal is to identify tumor cell-intrinsic transcriptional programs that are critical for dormancy-to-emergence transition and progressive growth of established metastases in breast cancer. In the proposed study, we hypothesize that dormancy-to- emergence switch and progressive metastatic growth of breast cancer cells require the action of Myocardin- related transcription factor (MRTF), a transcriptional coactivator of serum-response factor (SRF). To test this hypothesis, we propose two specific aims. In Aim 1, we will conduct genetic and pharmacological proof-of- concept studies to establish the role of MRTF/SRF transcriptional axis in regulation of dormancy and metastatic growth of breast cancer cells. Aim 2 will test whether MRTF/SRF activity promotes metastatic growth of breast cancer cells through both tumor-intrinsic and –extrinsic mechanisms. The proposed studies will employ a highly comprehensive experimental strategy integrating inducible functional disruption and pharmacological intervention strategies, intravital imaging of tumor cell activity at metastatic sites, organotypic models of lung and liver tumor microenvironment to study tumor dormancy, mouse model studies, use of patient-derived organoids and clinical samples of BC, and multiplexed quantitative IHC. A successful completion of these studies will establish MRTF as a novel regulator of dormancy-emergence behavior of breast cancer cells with mechanistic details, and provide proof-of-concepts for pharmacological intervention of MRTF as a novel strategy to induce dormancy and curb metastatic growth in breast cancer.